The main goal of our IPCAVD Program grant is to evaluate, in humans, recombinant Env immunogens that are specifically designed to activate B cells that produce broadly neutralizing antibodies (bnAbs) against the CD4-binding site (CD4-BS) of the HIV Env. Our studies are based on two key observations made by the participants of our Program: a) the identification of the earliest roadblock in the elicitation of anti-CD4-BS bnAbs, namely the inability of recombinant Env to engage and activate germline B cell receptors (BCRs) that give rise to such antibodies; and b) the development of a recombinant Env protein that is uniquely capable of doing exactly that i.e., to activate B cells expressing germline BCRs of some of the most broad and potent anti-HIV neutralizing antibodies known, namely the 'VRCOI' class antibodies. Our proposal takes advantage of our excellent expertise in immunogen-design; an unparalleled expertise in B cell immunology; the development of tools that allow for the deep-sequencing of vaccine-specific BCRs during the course of immunization; the availability of the appropriate animal models to validate pre-clinically the ability of our immunogens to stimulate the expansion of B cells expressing the desired BCRs; and the unique expertise of the HVTN to conduct clinical testing of HIV vaccines. Specifically, our team is composed of individuals with diverse expertise that have a documented record of collaboration and have directed and participated in large multi-component grants. Dr.- Stamatatos (overall PI of this IPCAVD Program and Leader of Project One) at Seattle BioMed is leading our 'immunogen design' efforts. Dr. Sather also at the Seattle BioMed, Dr. Nussenzweig (The Rockefeller University) and Dr. Rawlings at UW/Seattle Children's are co-leaders of the 'preclinical evaluation' of our immunogens (Project Two). Dr. Julie McElrath (Fred Hutchinson Center and the HVTN) will oversee the clinical testing of our selected immunogen (Project Four).